Posted by JohnX2 on March 20, 2002, at 21:42:40
In reply to Increased 5-HT2a and Suicide - JohnX, CamW, et al., posted by SLS on March 20, 2002, at 8:30:14
This seems consistent with other things I have read.I still think a clean medicine that directly agonizes the 5ht-1a receptor and antognizes the 5ht-2a receptor would be interesting. Yeah, it would not be "next generation" as it is still serotonergic. But maybe it is a step up from the SSRIs by being a bit "smarter" at the serotonin system. I think it took some feedback from the SSRIs to figure out what made them "tick" and what made them "suck". Maybe it would have the 2/3 hit rate on depression of the SSRIs and the side effect profile would be much more benign and we could get a faster response time. I would think that perhaps the medicine may even act faster/be more efficacious since the 5ht-2a receptor would not struggle to be downregulated. Also if the medicine was direct acting agonist at the post synaptic 5ht-1a receptors we may get a faster run. Also we are somewhat bypassing the time to dowregulate the somatodendric autoreceptors. I could potentially see more patient compliance, WAY fewer side effects, quicker response time, etc. This would still leave a lot of TRD patients I believe (as serotonin is not the root of all evil). Maybe I am dreaming....but I still see a huge market for such a medicine.
John
> I'll let you guys with more brain power review this.
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> 5-HT2a receptors?
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> Serzone
> Remeron
> Zyprexa
> Risperdal
> Geodon
>
>
> - Scott
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> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11870006&dopt=Abstract
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> Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims.
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> Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Pandey SC, Pesold C, Roberts RC, Conley RR, Tamminga CA.
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> Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 60612, USA. gnpandey@psych.uic.edu
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> OBJECTIVE: Abnormalities of serotonin (5-HT) receptor subtypes have been observed in the postmortem brains of adult suicide victims; however, their role in teenage suicide is unexplored. The authors examined whether 5-HT(2A) receptor subtypes are altered in the postmortem brains of teenage suicide victims. METHOD: Levels of 5-HT(2A) receptors were determined through examination of [(125)I] LSD binding, protein expression (by use of Western blotting with a specific 5-HT(2A) receptor antibody), and mRNA (by means of quantitative reverse transcription polymerase chain reaction) in the prefrontal cortex, hippocampus, and nucleus accumbens of 15 teenage suicide victims and 15 normal matched teenage subjects. The cellular localization of the 5-HT(2A) receptors was determined by means of gold immunolabeling. RESULTS: The authors observed significantly higher [(125)I]LSD binding in the prefrontal cortex and greater protein expression and mRNA levels in the prefrontal cortex and hippocampus but not in the nucleus accumbens of suicide victims, compared with normal subjects. Greater protein expression was localized on pyramidal cells in cortical layer V but not in other cortical layers or in the surrounding neuropil of the prefrontal cortex of teenage suicide victims. CONCLUSIONS: The evidence indicates higher levels of 5-HT(2A) receptor, protein, and mRNA expression in the prefrontal cortex and hippocampus, which have been implicated in emotion, stress, and cognition. There was no higher level in the nucleus accumbens, which has been implicated in drug dependence and craving. Our findings suggest that a higher level of 5-HT(2A) receptors may be one of the neurobiological abnormalities associated with teenage suicide.
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> PMID: 11870006 [PubMed - indexed for MEDLINE]
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> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10418694&dopt=Abstract
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> Biol Psychiatry 1999 Jul 15;46(2):196-201
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> Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.
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> Du L, Faludi G, Palkovits M, Demeter E, Bakish D, Lapierre YD, Sotonyi P, Hrdina PD.
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> Institute of Mental Health Research at Royal Ottawa Hospital, Ontario, Canada.
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> BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.
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> PMID: 10418694 [PubMed - indexed for MEDLINE]
poster:JohnX2
thread:98991
URL: http://www.dr-bob.org/babble/20020318/msgs/99118.html